Cystatin F as a neuroimmune effector in CNS inflammation and neurodegeneration

Cystatin F (CST7) has emerged as one of the most consistently upregulated genes identified in transcriptomic and spatial profiling studies of the central nervous system (CNS), particularly within activated microglia and other neuroimmune cell populations. Once regarded primarily as a marker of immune activation, accumulating evidence suggests that the encoded protein, cystatin F, may play a more active role in regulating neuroimmune function through its established ability to modulate lysosomal cysteine proteases. This review synthesizes current knowledge of cystatin F biology and examines its growing relevance across aging, neurodegenerative disease, and CNS inflammation. We first summarize the molecular biology of cystatin F, including its unique intracellular processing, activation, and regulation of cathepsin activity. We then discuss evidence supporting CST7 as a conserved marker of activated neuroimmune cells across diverse immune populations and disease-associated cellular states. Next, we review findings implicating CST7 across neurodegenerative diseases, highlighting remarkable consistency across distinct pathological contexts. Finally, we examine potential mechanisms linking cystatin F to lysosomal homeostasis, antigen presentation, inflammatory signaling, and cell death pathways. Although direct functional studies within the CNS remain limited, the convergence of biochemical, immunological, and transcriptomic evidence suggests that cystatin F is well positioned to influence neuroimmune responses rather than merely reflect them. Defining the precise role of cystatin F in CNS immunity may therefore provide new insight into the regulation of neuroinflammation and identify novel opportunities for therapeutic intervention across a broad spectrum of neurological diseases.